Application of a commercial digestive supplement formulated with enzymes and probiotics in lactase non-persistence management.

Strategies to avoid lactose malabsorption, which affects 70% of the world's population, are focused on the restriction of milk and dairy products or the use of non-human ß-galactosidases or probiotics endowed with ß-galactosidase activity added at mealtime. Our evaluation of a commercial blend of probiotics and enzymes (protease, lactase, lipase and amylase) and its potential application in lactase non-persistence management is described in this work. Recommended amounts (460-1000 mg) of the commercial probiotics-enzyme blend were shown to be adequate for performing in vitro lactose hydrolysis in standard solutions (0.25-5%) and commercial dairy products, namely milks (5% lactose) and yogurts (3% lactose), reaching hydrolysis values between 44 and 96%. According to these percentages, the use of the enzymatic preparation would guarantee the intake of less than 12 g, the recommendation of the EFSA for lactose intolerance. Furthermore, formation of prebiotic galactooligosaccharides was also detected, increasing the potential benefits of the enzymatic preparation in the gastrointestinal system.

Deprotection-Induced Morphology Transition and Immunoactivation of Glycovesicles: A Strategy of Smart Delivery Polymersomes.

We proposed the deprotection-induced block copolymer self-assembly (DISA); that is, the deprotection of hydroxyl groups resulted in in situ self-assembly of glycopolymers. In the previous studies, block copolymers soluble in common organic solvents were employed as the starting material. In this paper, by using the protected glyco-block containing preassembled glycovesicles in water as the starting material, we moved forward and made two exceeding achievements. First, we have observed a deprotection-induced morphology transition triggered by alkali in water. The carbohydrate-carbohydrate interactions were considered to contribute to such a morphology transition during deprotection. Second, lipase was found to be an efficient enzymatic trigger in the sugar deprotection, which motivates the immune-application of this morphology transition process. When lipase and a model antigen, ovalbumin (OVA), were encapsulated inside the glycovesicles, the deprotection of sugars by lipase induced the transition of vesicles to micelles and the lipase and OVA were released accordingly. When glycovesicles were internalized by dentritic cells (DCs), the lipase from lysosomes efficiently induced the release of OVA and presentation of antigen to T cells. During the process, lysosomal lipase performed as a trigger on the deprotection of sugars and the release of protein without any other reagents. The significance of this design is that as a delivery vehicle, the protected glycovesicles not only avoided unnecessary immune activation but also worked with the released OVA together; that is, the glycovehicle successfully activated DCs and improved the presentation efficiency of T cells remarkably.

Pancreatic enzyme replacement therapy (PERT) in children with persistent diarrhea: avoidance of elemental diet need, accessibility and costs.

BACKGROUND AND OBJECTIVES: Persistent diarrhea has been proven to cause pancreatic exocrine insufficiency, due to decreased stimulation to the pancreas caused by prolonged mucosal injury. Pancreatic enzyme replacement therapy (PERT) given in conjunction to regular treatment is thought to be beneficial in replacing this pancreatic enzyme deficiency, avoiding the need of elemental diet. This study aims to evaluate the benefit of PERT in chil-dren with persistent diarrhea. METHODS AND STUDY DESIGN: This is a randomized, two double-blind parallel group, placebo-controlled clinical trial to evaluate the effects of pancreatic enzyme supplementation in persistent diar-rhea. Children age 6-60 months were recruited from pediatric inpatient and outpatient units of five hospitals in Jakarta. Subjects was randomly assigned to either pancreatic enzyme 8371 USP unit of lipase or placebo, 3 times daily for 1 month, as an adjunctive therapy to standard treatment. Subjects were then reevaluated at 2 weeks and 4 weeks interval after administration of enzyme or placebo. Variables observed were length of diarrhea after the start of intervention, change in serum prealbumin, and change in FE-1 between week 0 and week 4. RESULTS: Pan-creatic enzyme supplementation shortens the length of diarrhea by 7 days in the intervention group compared to placebo (p=0.019). Serum prealbumin and FE-1 shows trend that favors the intervention group, although not sta-tistically significant (p>0.05). CONCLUSION: PERT is clinically effective in reducing the length of diarrhea, thus minimizing the need, accessibility and costs of an elemental diet.

Encapsulation, protection, and delivery of bioactive proteins and peptides using nanoparticle and microparticle systems: A review.

There are many examples of bioactive proteins and peptides that would benefit from oral delivery through functional foods, supplements, or medical foods, including hormones, enzymes, antimicrobials, vaccines, and ACE inhibitors. However, many of these bioactive proteins are highly susceptible to denaturation, aggregation or hydrolysis within commercial products or inside the human gastrointestinal tract (GIT). Moreover, many bioactive proteins have poor absorption characteristics within the GIT. Colloidal systems, which contain nanoparticles or microparticles, can be designed to encapsulate, retain, protect, and deliver bioactive proteins. For instance, a bioactive protein may have to remain encapsulated and stable during storage and passage through the mouth and stomach, but then be released within the small intestine where it can be absorbed. This article reviews the application of food-grade colloidal systems for oral delivery of bioactive proteins, including microemulsions, emulsions, nanoemulsions, solid lipid nanoparticles, multiple emulsions, liposomes, and microgels. It also provides a critical assessment of the characteristics of colloidal particles that impact the effectiveness of protein delivery systems, such as particle composition, size, permeability, interfacial properties, and stability. This information should be useful for the rational design of medical foods, functional foods, and supplements for effective oral delivery of bioactive proteins.

Options for addressing exocrine pancreatic insufficiency in patients receiving enteral nutrition supplementation.

Patients with exocrine pancreatic insufficiency (EPI) have suboptimal secretion of pancreatic digestive enzymes and experience a range of clinical symptoms related to the malabsorption of fat. In patients with EPI unable to meet their nutritional requirements, enteral nutrition (EN) support is used to augment nutritional status. In addition to protein and carbohydrate, EN formulas contain fats as a calorie source, as well as vitamins and minerals to help prevent nutritional deficiencies related to malabsorption. Semielemental enteral nutrition formulas are advantageous as they contain hydrolyzed protein, shorter chain carbohydrates, and may contain medium chain triglycerides as a fat source. However, severely pancreatic insufficient patients may be unable to absorb complex long-chain triglycerides provided by EN formulas due to insufficient pancreatic lipase; replacement pancreatic enzyme products are recommended for these patients. Currently, none of the FDA-approved pancreatic enzyme replacement therapy (PERT) products are indicated for use in patients receiving enteral nutrition and administration of enzymes by mixing into enteral nutrition formula is not supported by guidelines as this route is associated with risks. RELiZORB (immobilized lipase) is a novel in-line digestive cartridge that has been designed to address the unmet need for PERT in patients receiving enteral nutrition. RELiZORB efficacy and compatibility with a range of commercially available polymeric and semielemental formulas with varying nutrient, caloric content, and triglyceride chain lengths have been demonstrated. In most formulas, RELiZORB efficiently hydrolyzed greater than 90% of fats within the formula into absorbable fatty acids and monoglycerides.

Increased Fat Absorption From Enteral Formula Through an In-line Digestive Cartridge in Patients With Cystic Fibrosis.

OBJECTIVES: Supplemental enteral nutrition (EN) is used by approximately 12% of people with cystic fibrosis (CF). The objective of this study was to evaluate the safety, tolerability, and fat absorption of a new in-line digestive cartridge (Relizorb) that hydrolyzes fat in enteral formula provided to patients with CF. METHODS: Patients with CF receiving EN participated in a multicenter, randomized, double-blind, crossover trial with an open-label safety evaluation period. Plasma omega-3 fatty acid (FA) concentrations were measured and used as markers of fat absorption. Gastrointestinal symptoms were recorded to evaluate safety and tolerability. Information regarding the effect of EN on appetite and breakfast consumption was also collected. RESULTS: Before study entry, participants had received EN for a mean of 6.6 years at a mean volume of approximately 800 mL, yet had a mean body mass index of only 17.5 kg/m and omega-3 FA plasma concentrations were only 60% of levels found in normal healthy subjects. Compared with placebo, cartridge use resulted in a statistically significant 2.8-fold increase in plasma omega-3 FA concentrations. There were no adverse experiences associated with cartridge use, and a decrease in the frequency and severity of most symptoms of malabsorption was observed with cartridge use. Participants reported increased preservation of appetite and breakfast consumption with cartridge use compared with their pre-study regimen. CONCLUSIONS: Use of this in-line digestive cartridge was safe and well tolerated, and resulted in significantly increased levels of plasma omega-3 FA used with enteral formula, suggesting an overall increased fat absorption.

Characterization and Applications of Marine Microbial Enzymes in Biotechnology and Probiotics for Animal Health.

Marine microorganisms have been recognized as potential sources of novel enzymes because they are relatively more stable than the corresponding enzymes derived from plants and animals. Enzymes from marine microorganisms also differ from homologous enzymes in terrestrial microorganisms based on salinity, pressure, temperature, and lighting conditions. Marine microbial enzymes can be used in diverse industrial applications. This chapter will focus on the biotechnological applications of marine enzymes and also their use as a tool of marine probiotics to improve host digestion (food digestion, food absorption, and mucus utilization) and cleave molecular signals involved in quorum sensing in pathogens to control disease in aquaculture.

Functional characterization of recombinant major envelope protein (rB2L) of orf virus.

Orf, or contagious ecthyma, a highly contagious transboundary disease of sheep and goats, is caused by a double-stranded DNA virus (ORFV) belonging to the genus Parapoxvirus of the family Poxviridae. The ORFV genome encodes the major envelope proteins B2L and F1L, which have been found to be highly immunogenic and have multiple functional characteristics. In order to investigate the functional properties of the B2L protein, in this study, the B2L gene of ORFV strain 59/05, encoding recombinant mature B2L (aa 1M-D334), was produced as a fusion protein in Escherichia coli. The functional characteristics of purified rB2L fusion protein (~60 kDa) were evaluated in vivo and in vitro, showing that this protein had lipase and immunomodulatory activities. Immunization trials involving laboratory animals (mice, rabbits and guinea pigs) using either constant or graded doses of rB2L fusion protein with or without adjuvants (FCA, alum) as well as co-administration with candidate rErns-Ag protein of classical swine fever virus (CSFV) indicated that the rB2L protein is immunogenic and has immunomodulatory properties. This study shows the potential utility of the rB2L protein as a safe and novel adjuvant in veterinary vaccine formulations.

Should we Investigate Gastroenterology Patients for Pancreatic Exocrine Insufficiency? A Dual Centre UK Study.

BACKGROUND AND AIMS: Pancreatic exocrine insufficiency may be under recognised in gastroenterological practice. We aimed to identify the prevalence of pancreatic insufficiency in secondary care gastroenterology clinics and determine if co-morbidity or presenting symptoms could predict diagnosis. A secondary aim was to assess response to treatment. METHODS: A dual centre retrospective analysis was conducted in secondary care gastroenterology clinics. Patients tested for pancreatic exocrine insufficiency with faecal elastase-1 (FEL-1) between 2009 and 2013 were identified in two centres. Demographics, indication and co-morbidities were recorded in addition to dose and response to pancreatic enzyme replacement therapy. Binary logistic regression was used to assess if symptoms or co-morbidities could predict pancreatic insufficiency. RESULTS: 1821 patients were tested, 13.1% had low FEL-1 (<200µg/g). This prevalence was sub-analysed with 5.4% having FEL-1 100-200µg/g (mild insufficiency) and 7.6% having faecal elastase readings <100µg/g. Low FEL-1 was most significantly associated with weight loss or steatorrhoea. Co-morbidity analysis showed that low levels were significantly associated with excess alcohol intake, diabetes mellitus or human immunodeficiency virus; 80.0% treated with enzyme supplements reported symptomatic benefit with no difference in response between high and low dose supplementation (p=0.761). CONCLUSION: Targeting the use of FEL-1 in individuals with specific symptoms and associated conditions can lead to improved recognition of pancreatic exocrine insufficiency in a significant proportion of secondary care patients. Intervening with lifestyle advice such as smoking cessation and minimising alcohol intake could improve outcomes. In addition, up to 80% of patients with low faecal elastase respond to supplementation.

Enzymatic Polymerization of an Ibuprofen-Containing Monomer and Subsequent Drug Release.

Novel ibuprofen-containing monomers comprising naturally occurring and biocompatible compounds were synthesized and subsequently polymerized via enzymatic methods. Through the use of a malic acid sugar backbone, ibuprofen was attached as a pendant group, and then subsequently polymerized with a linear aliphatic diol (1,3-propanediol, 1,5-pentanediol, or 1,8-octanediol) as comonomer using lipase B from Candida antarctica, a greener alternative to traditional metal catalysts. Polymer structures were elucidated by nuclear magnetic resonance and infrared spectroscopies, and thermal properties and molecular weights were determined. All polymers exhibited sustained ibuprofen release, with the longer chain, more hydrophobic diols exhibiting the slowest release over the 30 d study. Polymers were deemed cytocompatible using mouse fibroblasts, when evaluated at relevant therapeutic concentrations. Additionally, ibuprofen retained its chemical integrity throughout the polymerization and in vitro hydrolytic degradation processes. This methodology of enzymatic polymerization of a drug presents a more environmentally friendly synthesis and a novel approach to bioactive polymer conjugates.

Pancreatic Enzyme Replacement Therapy and Coefficient of Fat Absorption in Children and Adolescents With Cystic Fibrosis.

OBJECTIVES: Pancreatic enzyme replacement therapy (PERT) is the proven therapy to substantially reduce fat malabsorption in patients with cystic fibrosis (CF). Few details of the daily practice regarding PERT and the resulting coefficient of fat absorption (CFA) are known. We therefore recorded the PERT and CFA in a large cohort of pancreatic insufficient pediatric patients with CF. METHODS: We retrospectively studied 1719 completed 3-day dietary food records, including the pancreatic enzyme intake registrations, and 1373 CFA assessments of 224 patients with CF, ages 0-17 years. The clinical characteristics, PERT, expressed as an intake of lipase unit (LU) per gram of fat per day and LU per kilogram per day, and the CFA were described for the group as a whole and separately for those on enteral tube feeding. Cross-sectional relationship between the CFA and the LU per gram of fat per day and LU per kilogram per day were determined for each year of age. We also addressed the effect of the interventions done in patients with CFA outcomes <85%. RESULTS: The LU per gram of fat per day was relatively stable throughout the age groups, whereas the LU per kilogram per day fell markedly with age. The median CFA in the age group 17 varied between 86% and 91%, however, with a CFA below 85% in 325 of 1373 (24%) of the measurements. No relationship was found between PERT and CFA. The patients with persistent CFA less than 85% had significant lower z scores weight for age and weight for height (P = 0.01) than those with CFA at least 85%. CONCLUSIONS: In this study population, no correlation between an enzyme dosage and the degree of fat malabsorption was found; however, a CFA below 85% was found in 24% of the measurements.

Nutrition and pancreatic enzyme intake in patients with cystic fibrosis with distal intestinal obstruction syndrome.

BACKGROUND: The etiology of distal intestinal obstruction syndrome (DIOS) remains unclear. Food intake and pancreatic enzyme replacement therapy (PERT) are often blamed for its occurrence. This study evaluates the nutrition intake and PERT of patients with cystic fibrosis (CF) at a first episode of DIOS. METHODS: All patients with CF perform annually a 3-day intake diary to evaluate their caloric, protein, fat, dietary fiber, liquid, and PERT intake. Patients diagnosed with a first episode of DIOS (n = 12) retrospectively completed an intake diary of the 3 days preceding the DIOS episode supervised by an expert dietitian. RESULTS were compared with those of 1 year before and also with 36 CF controls matched for age, sex, genotype, and disease severity. All were pancreatic insufficient. RESULTS: A first DIOS episode was diagnosed in 12 patients with CF. Only the absolute median fat intake (P = .015) and pancreatic enzyme intake (P = .035) were higher at the time of the DIOS attack in comparison to the preceding year. This could result from the difference in data collection or from the recommendations to increase fat intake and concomitant enzyme intake, since this trend was also found in the control group. The significant difference disappears when enzyme intake is expressed as units of lipase/g of fat. No other significant dietary differences were found. CONCLUSIONS: This study provides no indications for a potential role of nutrition factors or pancreatic enzymes in the first occurrence of DIOS.

Lipase Supplementation before a High-Fat Meal Reduces Perceptions of Fullness in Healthy Subjects.

BACKGROUND/AIMS: Postprandial symptoms of fullness and abdominal discomfort are common after fatty meals. Gastric lipases hydrolyze 10% to 20% of dietary triglycerides during the stomach trituration period of digestion. The aim of this study was to evaluate the effects of acid-resistant lipase on upper gastrointestinal symptoms, including fullness and bloating, as well as on gastric myoelectrical activity after healthy subjects ingested a high-fat, liquid meal. METHODS: This study utilized a double-blind, placebo-controlled, crossover design with 16 healthy volunteers who ingested either a capsule containing 280 mg of acid-resistant lipase or a placebo immediately before a fatty meal (355 calories, 55% fat). Participants rated their stomach fullness, bloating, and nausea before and at timed intervals for 60 minutes after the meal. Electrogastrograms were obtained to assess the gastric myoelectrical activity. RESULTS: Stomach fullness, bloating, and nausea increased significantly 10 minutes after ingestion of the fatty meal (p<0.01), whereas normal gastric myoelectrical activity decreased and tachygastria increased (p<0.05). With lipase, reports of stomach fullness were significantly lower compared with placebo (p<0.05), but no effect on gastric myoelectrical activity or other upper gastrointestinal symptoms was observed. CONCLUSIONS: The high-fat meal induced transient fullness, bloating, nausea, and tachygastria in healthy individuals, consistent with postprandial distress syndrome. Acid-resistant lipase supplementation significantly decreased stomach fullness.

Gastrointestinal symptoms before and after total pancreatectomy with islet autotransplantation: the role of pancreatic enzyme dosing and adherence.

OBJECTIVES: In a large cohort of subjects undergoing total pancreatectomy with islet autotransplantation (TPIAT), we assessed the prevalence and duration of gastrointestinal (GI) symptoms before and after the procedure to determine the impact of enzyme adherence on GI symptoms. METHODS: Three hundred fifty-six preoperative and postoperative questionnaires were collected from 184 subjects between ages of 5 and 66 years who underwent TPIAT between 2008 and 2011 at the University of Minnesota. Questionnaires were analyzed for self-reported frequency and severity of GI symptoms, pancreatic enzyme usage, and glycemic variability index (GVI). RESULTS: After surgery, patient-reported steatorrhea increased whereas constipation decreased. Gastrointestinal symptoms interfered with daily activity in 44% to 69% of subjects, before and after surgery, despite high reported enzyme adherence. Postoperatively, more than 79% of subjects reported consistent use of enzymes at all meals. Presence of GI symptoms did not vary with adherence. The GVI of 2 had a 2.8-fold increased odds of steatorrhea (95% confidence interval, 1.1-7.0) compared with GVI of 0. CONCLUSIONS: Gastrointestinal symptoms were common after TPIAT; ongoing management is needed. Enzyme nonadherence was not a major contributor to diarrhea/steatorrhea in this cohort. Glycemic variability was closely associated with steatorrhea; poor response to enzyme replacement may complicate diabetes management.

The effect of oral pancreatic enzyme supplementation on the course and outcome of acute pancreatitis: a randomized, double-blind parallel-group study.

CONTEXT: Pancreatic exocrine insufficiency is a significant problem after acute pancreatitis. OBJECTIVE: To evaluate whether oral pancreatic enzyme supplementation improves the recovery of pancreatic exocrine function and to explore the efficacy, safety and tolerability of pancreatic enzyme supplementation in patients during the refeeding period after acute pancreatitis. DESIGN: Prospective double-blind, placebo controlled, randomized study. PATIENTS: The sudy included 56 patients with acute pancreatitis. MAIN OUTCOME MEASURES: Primary efficacy variable was recovery from pancreatic exocrine insufficiency. Secondary objectives were body weight, abdominal pain, course of APACHE II score, patient's symptoms and quality of life. RESULTS: Twenty of the 56 patients showed low fecal elastase values indicating pancreatic exocrine insufficiency after acute pancreatitis. Median time to recovery from exocrine pancreatic insufficiency was 14 days in the enzyme supplementation group and 23 days in the placebo group but overall differences for primary and all but one secondary endpoint did not reach statistical significance. However, a positive tendency in favour of enzyme supplementation was found for quality of life parameters (FACT-Pa) in all subscores. There were no relevant differences between placebo and oral pancreatic enzyme supplementation detected with respect to safety and tolerability. CONCLUSION: Enzyme supplementation positively effects the course of acute pancreatitis if administered during the early refeeding phase after acute pancreatitis. There is evidence that oral pancreatic enzyme supplementation has a positive impact on the course of the disease and the global health status (less weight loss, less flatulence, improved quality of life). Oral pancreatic enzyme supplementation was safely administered and can be added to the treatment regimen of patients in a refeeding status after severe acute pancreatitis.

[Cholestasis and pancreatic insufficiency: how to start treatment?].

The article presents a detailed analysis of pathogenesis and clinical manifestation of secondary pancreatic excretory insufficiency due to disorders of bile production and choleresis. Pathogenesis of hepatogenic (chologenic) pancreatic insufficiency considered in view of impairment of bile acids' different functions in cholestasis. Authors review pathology of liver and bile ducts resulted in steatorrhea. It was conducted pathogenetic substantiation treatment tactics of patients, which have a combination of cholestasis and secondary pancreatic insufficiency.

Maldigestion from pancreatic exocrine insufficiency.

Pancreatic exocrine insufficiency (PEI) is one of the long-term consequences of chronic pancreatitis (CP). Majority of patients with PEI were undiagnosed or undertreated. Inadequately treated or subclinical severe PEI causes malnutrition and may pose the patients at risk of premature atherosclerosis and cardiovascular events. Indication of pancreatic enzyme replacement therapy (PERT) is patients with severe PEI, as indicated by the presence of steatorrhea, diarrhea, weight loss, fecal fat > 7 g/day, (13) C-mixed triglyceride breath test < 29%, fecal elastase < 100 ug/g stool, imaging or endoscopic findings of pancreatic ductal dilatation or calculi, and eight endosonographic criteria of CP. The mainstay treatment of PEI is PERT. Dietary fat restriction is unnecessary. PERT with lipase > 40,000 U per meal is recommended. Enteric-coating may be preferred to conventional enzymes because of the availability of high-dose preparations and no need of acid suppression co-therapy. Administration of enzymes with meals is proven to be the most effective regimen. Response to PERT should be measured by the improvement of patients' symptoms, nutritional status, and, in selected cases, by fecal fat or (13) C-mixed triglyceride breath test. Patients unresponsive to PERT should be checked for compliance, increase the dose of lipase to 90,000 units/meal or co-therapy with proton pump inhibitor. In patient with previous gastrointestinal surgery that may interfere enzyme-food mixing, opening the capsules and administering the enzyme granules with meals. Finally, search for small intestinal bacterial overgrowth syndrome and other causes of small bowel malabsorption.

Maximal daily dose of pancreatic enzyme replacement therapy in infants with cystic fibrosis: a reconsideration.

The current recommendations for dosing of pancreatic enzyme replacement therapy (PERT) in infants with cystic fibrosis (CF) were made using a limited evidence base. The per meal recommended dose was extrapolated from dosing guidelines for older patients into a maximal daily dose for infants. We discuss why this maximal daily dose recommendation may be insufficient for young infants with CF, although the optimal dose of PERT for infants with CF remains unknown.

Effects of fungal pancreatic enzymes on the function of islet cells in Syrian golden hamsters.

CONTEXT: Our previous studies showed that porcine pancreatic enzymes in Syrian golden hamsters with peripheral insulin resistance normalizes the plasma insulin level, reduces the size of enlarged islets and inhibits the increased DNA synthesis in the beta-cell of islets. OBJECTIVE: In order to exclude the possibility that these effects was attributed to some contaminants of this crude material, we tested the effect of purified fungal pancreatic enzyme (FPE) that contains primarily amylase and lipase without (FPE) and with addition of chymotrypsin (FPE+chy). MATERIAL AND METHODS: In a pilot study we tested the effect of different doses of FPE given in drinking water on insulin level, islet size and DNA synthesis of islet cells in hamsters with induced peripheral insulin resistance by a high fat diet. The most effective dose of FPE on these parameters was used in a long-term experiment with FPE and FPE+chy in hamsters fed a high-fat diet for 36 or 40 weeks. RESULTS: In the pilot study a dose of 2 g/kg body weight was found to be optimal for controlling the body weight, normalizing plasma insulin level, the size of islets, the DNA synthesis and the number of insulin cells in the islets. These data were produced in the long-term study, where steatorrhea was also inhibited. Addition of chymotrypsin had no effects on these parameters. CONCLUSION: Pancreatic lipase and amylase appear to be responsible for the observed effects and offer a safe and effective natural product for the treatment of pancreatic diseases, including acute pancreatitis, chronic pancreatic, cystic fibrosis and any conditions associated with peripheral insulin resistance, including obesity and type 2 diabetes. The possible mechanism of the action is discussed.